The brains of demented Alzheimer's disease (AD) patients are characterized by abundant senile plaques (Sps) and neurofibrillary tangles (NFTs). Further, the quantity of NFTs correlates with the dementia in AD, and cerebrospinal fluid (CSF) tau levels are abnormally high in most AD patients consistent with the fact that the subunits of paired helical filaments (PHFs) in AD NFTs are altered forms of tau (PHFtau). Despite the presence of small numbers of NFTs in the brains of non-demented elderly subjects, the molecular and cellular substrates of age-related, mild cognitive impairments in otherwise normal elderly individuals are not known. Although PHFtau is abnormally phosphorylated, we showed that biopsy derived normal adult human tau is phosphorylated at nearly all of the sites previously identified in PHFtau, albeit to a lesser extent. Further, biopsy derived tau proteins are rapidly dephosphorylated at sites that are retained in PHFtau. Thus, differences in the phosphorylation sites and/or state of normal human tau versus PHFtau may reflect the differential activities of phosphatases in the control versus AD brain. Indeed, deficient protein phosphatase 2A (PP2A) activity has been implicated in the formation of PHFtau, and alterations in the accessory, catalytic and regulatory subunits of PP2A could be part of a "final common neurodegenerative pathway" leading to the generation of PHFtau, NFTs and the death of neurons in AD. Since similar mechanisms also might account for milder cognitive impairments in otherwise normal elderly individuals, we will test the hypothesis that alterations in PP2A subunits may play a role in the pathogenesis of neurofibrillary lesions in normal aging, and that low levels of neurofibrillary lesions may contribute to mild cognitive impairments in the elderly. These studies will be conducted in well characterized elderly members of a "religious orders study cohort" with no or mild cognitive impairments versus dementia due to AD.